21-nitro pregnane compounds and process for the production thereof



United States Patent Ofifice 3,035,067 Patented May 15, 1962 The presentinvention relates to cyclopentanophenanthrene derivatives and to aprocess for the production thereof.

More particularly the present invention relates to novel 21-nitro-A-pregnen-3,20-dione derivatives which may include one or more of thefollowing substituents, 17oc-hydroxy, 1 l-keto, 9a-halogen (bromine,chlorine or fluorine) and an additional double bond at C-1(2).

The new 21-nitro A -pregnen-3,ZO-diones, substituted or not, showbiological effects which make them potent valuable drugs;2l-nitro-progesterone differs from progesterone in its superiorprogestational activity; 21-nitro-A pregnen-3,l l,20-trione,9u-halo-2l-nitro-A -pregnen-3,1 l, ZO-triones and 2l-nitro-A-pregnen-17a-ol-3,20-dione show anti-estrogenie activity; 2l-nitro-A-pregnen-17a-ol-3,11, 20-trione, 21-nitro-A-pregnadien-17u-0l-3,11,20-trione, as Well as their 9u-halo analogues,have a great anti-inflammatory effect.

In accordance with our invention it has been discovered that the novel21-nitro pregnene derivatives previously and hereinafter described indetail may be prepared from the corresponding 21-hydroxy pregnane seriescompounds by reacting the side chain thereof to selectively reduce theZO-keto group of the starting compound to a 20-hydroxy group, bycleaving the glycol thus formed to form the corresponding aldehydegroup, by condensing the aldehyde group with nitromethane to form the2l-nitro-20-hydroxy derivative and finally by oxidizing the 20-hydroxygroup to a ZO-keto group.

The novel final compounds of the present invention may be illustrated bythe following formula:

CHzNOz Y Q m In the above equation Y, Z, X and R represent the samegroups as heretofore set forth.

Referring to the above equation a 21-hydroxy-3,20- diketo-A -pregnenecompound which may be substituted as indicated, or further unsaturatedat C-l(2) as indicated, was selectively reduced to transform the 20-ketogroup to a 20-hydroxy group. For this purpose a desirable reducing agentwas 0.5 molar equivalent excess over theory) of sodium borohydride.Preferably the reaction was carried out in an organic solvent such asmethanol at a low temperature of the order of 0 C. for a short period oftime of the order or one hour. The resultant 20,8,21-glycol, obtainedafter conventional separation and purification, was then cleaved withperiodic acid to give the aldehyde. Preferably the reaction withperiodic acid was performed in an organic solvent such as dioxane underan atmosphere of nitrogen and for a period of about 3 hours. Thealdehyde thus formed was then condensed with nitromethane preferably inthe presence of sodium methoxide to give the corresponding 21-nitro-ZO-ol derivative. The 21-hydroxy group of this last derivative wasthen oxidized with a conventional oxidizing agent for secondary hydroxylgroups such as chromic acid in acetic acid or chromium trioxide andsulfuric acid.

The following specific examples serve to illustrate but are not intendedto limit the present invention.

Example I A solution of 5 g. of desoxycorticosterone in 800 cc. ofmethanol was cooled to 0 C. and slowly treated with stirring with 0.5mol of sodium borohydride, while the temperature was maintained below 0C. The mixture was stirred for 1 hour further at 0 C., acidified withacetic acid, evaporated to dryness under reduced pressure and theresidue was extracted several times with hot benzene. The benzeneextract was washed with water, dried over anhydrous sodium sulfate andevaporated to dryness under reduced pressure. The residue was purifiedby chromatography on silica, thus giving A -pregnen-20,21-diol-3- one.

3.3 g. of this glycol was mixed with 200 cc. of dioxane and slowlytreated with 2.1 g. of periodic acid dihydrate, under stirring and underan atmosphere of nitrogen. The stirring was continued under nitrogen for3 hours further and then water was added. The precipitate formed wascollected, washed with water, dried and crystallized from =2benzene-hexane, thus producing the C-20 aldehyde, that is, 17-forrnyl-A-androsten-3-one.

A mixture of l g. of the above compond, 20 cc. of methanol and 0.8 cc.of nitromethane was slowly mixed with a solution of 0.6 g. of sodiummethoxide in 20 cc. of methanol, with stirring under an atmosphere ofnitrogen. The mixture was stirred for 16 hours under nitrogen and thendiluted with 40 cc. of ether. The precipitate formed was collected byfiltration, dried under vacuum, suspended in 100 cc. of 2 N hydrochloricacid and stirred for 30 minutes. The precipitate was collected and.chromatographed on washed alumina, thus yielding 21-nitro-A-pregnen-20-ol-3-one.

500 mg. of 21-nitroA -pregnen-20-ol-3-one was dissolved in 25 cc. ofacetone, cooled to C. and mixed with an oxidizing reagent prepared from200 mg. of chromium trioxide, 0.18 cc. of concentrated sulfuric acid and1 cc. of water, which reagent was added dropwise to the stirred solutionwhile the temperature of the mixture was kept at 0 C., and in the courseof 2 minutes. After stirring for minutes further at 0 C. the mixture wasdiluted with Water and extracted with ether. The extract was washed withwater, dried over anhydrous sodium sulfate and evaporated.Crystallization of the residue from acetone-hexane furnished 21-nitr0-A-pregnen-3,20-dione (21-nitro-progesterone).

In another experiment 21-nitro-A -pregnen--ol-3-one was oxidized equalsuccessfully by treating 500 mg. of the compound in 10 cc. of aceticacid with a solution of 200 mg. of chromic acid in 5 cc. of 80% aceticacid, stirring the mixture for 2 hours at room temperature, dilutingwith Water and working up the product as described above.

Example 11 When in the method of Example I the desoxycorticosterone wassubstituted by cortisone, there was obtained as final productZI-nitro-M-pregnen-17ot-o1-3,11, ZO-trione.

Example 111 When in the method of Example I the desoxycorticosterone wassubstituted by 9u-fiuoro-prednisone, there was obtained9a-fiuoro-21-nitr0-A -pregnadien-1704-01-3, 1 1, 20-trione.

Example IV Following the method described in Example I, A-pregnen-21-ol-3,11,20-trione was converted into ZI-nitrQ-A pregnen-3,11,20-trione; 9a-bromo-A -pregnen-21-o1-3, 1 1, 20-trione gave9a-brorno-21-nitro A -pregnen-3,11,20- trione; 9u-chloro-A-pregnen-21-ol-3,11,20-trione produced 9a-chloro-21-nitro-A-pregnen-3,11,20 trione; 9afluoro-A -pregnen-21-ol-3,11,20-trione gave9a-fluoro-21- ni1Io-A -pregnen-3,11,20-trione; A -pregnen-17u,21- diol-3,20-dione (compound 8" of Reichstein) gave 21-nitro-A -pregnen-17oc-O1-3 ,20-dione; 9a-bromo-cortisone yielded 9a-bromo-21-nitro-A-pregnen- 17 a-ol3,1 1,20-trione; 9a-chloro-cortisone gave9a-chloro-21-nitro-A pregnen-17a-ol-3,11,20-trione; 9u-fiuoro-cortisonegave 9afluoro-21-nitro-M-pregnen-17a-o1-3, 1 1,20-trione; prednisonegave 21-nitro-A -pregnadien-17a-o1-3,11,20-trione; 9a bromo-1prednisonegave 9a-bromo 2l-nitro-A -pregnadien-17a-ol-3,11,20-trione;9a-chloro-prednisone furnished 9a-chloro-2l-nitro-A-pregnadien-17a-o1-3,11,20- trione.

We claim:

1. A process for the production of 21-nitro-3,20-diketo- A -pregnenecomponds comprising reacting the corresponding 21-hydroxy compounds witha reducing agent to form the corresponding 20,21-g1yco1 derivatives,cleaving the glycol side chain of these derivatives to form thecorresponding 17-formyl compounds with periodic acid, condensing theforrnyl compounds with nitro methane to form the correspondingZO-hydroxy-Zl-nitro compounds and oxidizing the 20-hydroxy group thereofto a 20-keto group with chromic acid.

2. Compounds of the following formula:

wherein X is selected from the group consisting of :0 and hydrogen, Z isselected from the group consisting of hydrogen, bromo, fluoro andchloro, Y is selected from the group consisting of a double bond betweenC-1 and C-2 and a saturated linkage between C-1 and C-2 and R isselected from the group consisting of OH and hydrogen.

. 21-nitro-A -pregnen-2043-018-one. 21-nitro A -pregnen-20-p-o1-3, 1l-dione. 9a-bromo-2'1-nitro-A -pregnen-20fi-ol-3,1 l-dione.9a-chloro-21-nitro-A -pregnen-20,8-01-3,1 l-dione. 9afluoro-21-nitro-A-pregnen-205-01-3,1 l-dione. 21-nitro-A -pregnen-17a,20fi-diol-3-one.2l-nitro-A -pregnen-17,20B-ol-3,11-dione.

10. 9a-bromo-2l-nitro n pregnen-17a,20fi-diol-3,1 1- dione.

'11. 9oz chloro 21 nitro A pregnen 171x305- dio1-3,1 l-dione.

12. 9oz fluoro 21 nitro A pregnen 17a,20pdiol-3,1 l-dione. 7

l3. 21-nitro-A -pregnadien-17a,20/3-di0l-3 ,1 l-dicne.

14. 9a bromo 21 nitro A pregnadien 17a, 2OB-diol-3,11-dione.

15. 9oz chloro 21 nitro A pregnadien 170a, 20,8-diol3,l1-dione.

16. 9a fluoro 21 nitro A pregnadien 170L- 20,8-diOl-3,1l-di0116.

17. 21-nitro-progesterone.

18. 21-nitro-A -pregnen-3,1l-trione.

19. 9a-bromo-21-nitro-A -pregnen-3,11,20-trione.

20. 9a-chloro-21-nitro-A -pregnen-3,11,20-trione.

21. 9a-fiuoro-21-nitro-A -pregnen-3, 1 1,20-trione.

22. 21-nitro-A -pregnen-17a-o1-3,2O-dione.

23. 2l-nitro-A -pregnen-17a-ol-3,1 1,20-trione.

24. 9a bromo 21 nitro A pregnen 17a ol- 3,11,20-trione.

25. c chloro 21 nitro A pregnen 17oz ol- 3,11,20-trione.

26. 9a fiuoro 21 nitro A pregnen 17a ol- 3,1 1,20-trione.

27. 21 nitro A pregnadien 17a ol 3,11,20- tritone.

28. 9oz bromo 21 nitro A pregnadien L- ol-3,1 1,20-tritone.

29. 9oz chloro 21 nitro A pregnadien 17aol-3,1 1,20-trione.

30. 9a fiuoro 21 nitro A pregnadien 17wol-3,11,20-trione.

No references cited,

1. A PROCESS FOR THE PRODUCTION OF 21-NITRO-3,20-DIKETO$4-PREGNENECOMPOUNDS COMPRISING REACTING THE CORRESPONDING 21-HYDROXY COMPOUNDSWITH A REDUCING AGENT TO FORM THE CORRESPONDING 20,21-GLYCOLDERIVATIVES, CLEAVING THE GLYCOL SIDE CHAIN OF THESE DERIVATIVES TO FORMTHE CORRESPONDING 17-FORMYL COMPOUNDS WITH PERIODIC ACID, CONDENSING THEFORMYL COMPOUNDS WITH NITRO METHANE TO FORM THE CORRESPONDING20-HYDROXY-21-NITRO COMPOUNDS AND OXIDIZING THE 20-HYDROXY GROUP THEREOFTO A 20-KETO GROUP WITH CHROMIC ACID.
 2. COMPOUNDS OF THE FOLLOWINGFORMULA: